[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to retrospectively determine the risk factors and evaluate the management of bile leakage.
Three hundred and thirty-four patients who underwent hepatectomy for Child classification grade A liver disease, without biliary reconstruction and laparoscopic procedures, between 2003 and 2013 were included. Risk factors were identified using multivariate analysis.
Bile leakage was observed in 30 (9.0 %) patients. Multivariate analysis demonstrated that type of hepatectomy (segmentectomy 1, medial sectionectomy, anterior sectionectomy, or central bisectionectomy) and operating time was independent risk factors for bile leakage. Among 30 patients with confirmed bile leakage, central type leakage that was in communication with the biliary tree occurred in 23 (76.7 %) patients and peripheral type, which was not in communication with the biliary tree, in 7 (23.3 %) patients. Ten patients were treated with only drainage. Endoscopic or percutaneous transhepatic procedures were performed in 15 cases with central type leakage. Ablation treatment using ethanol or minocycline was mainly performed for peripheral type leakage. Four cases with central type leakage had strictures of the right hepatic duct. Two of them were treated with ablation treatment, portal vein embolization, or fistulojejunostomy. Median duration from diagnosis to end of therapy was 77 days (11-323) in central type and 44 days (6-123) in peripheral type leakage, respectively.
Complex hepatectomy and operating time are independent risk factors for postoperative bile leakage. Biliary exploration should be performed as soon as possible after diagnosis, because most bile leakage is the central type. Central type of bile leakage is sometimes refractory to therapy, needing various treatments and requiring a long time for recovery.
Preview · Article · Jul 2015 · World Journal of Surgery
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to retrospectively evaluate microbial examination of sputum on postoperative day one (POD1) and to determine risk factors for postoperative pneumonia (POP) after hepatectomy.
Two hundred ninety-four patients who expectorated sputum on POD1 after hepatectomy between 2003 and 2014 were investigated. Sputum samples were submitted for microbial examination. Risk factors for POP were identified using multivariable analysis.
One hundred fifty-eight (53.7 %) of 294 patients had bacteria in their sputum on POD1. POP was observed in 24 (8.2 %) patients, with increased mortality in the patients with POP (0.74 vs 12.5 %, p < 0.01). Multivariate analysis demonstrated that a Brinkman index of >400 and bacteria in sputum on POD1 were independent risk factors for POP. Bacterial homology in sputum obtained on POD1 and onset day of POP was found in 13 of the 24 (54.2 %) patients with POP. In particular, in 13 patients with POP caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa, homology was confirmed in 9 patients (69.2 %).
A Brinkman index ≥400 and bacteria in sputum on POD1 increased the risk of POP. Presence of bacteria in sputum on POD1 may be useful in determining early treatment against POP after hepatectomy.
Preview · Article · Jun 2015 · Journal of Gastrointestinal Surgery
[Show abstract][Hide abstract] ABSTRACT: We previously reported overexpression of heat-shock protein (HSP) 70 in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) using proteomic profiling and immunohistochemical staining (IHS). This suggested that HSP70 could be a molecular target for treatment of HCC.
Twelve patients with HCV-related HCC were enrolled in a phase 1 clinical trial. Dendritic cells (DCs) transfected with HSP70 mRNA (HSP70-DCs) induced by electroporation were injected intradermally. Patients were treated three times every 3 weeks. The number of HSP70-DCs injected was 1 × 10(7) as the lowest dose, then 2 × 10(7) as the medium dose, and then 3 × 10(7) as the highest dose. Immunological analyses were performed.
No adverse effects of grade III/IV, except one grade III liver abscess at the 3 × 10(7) dose, were observed. Thus, we added three more patients to confirm whether 3 × 10(7) is an appropriate dose. Eventually, we chose 3 × 10(7) as the recommended dose of DCs. Complete response (CR) without any recurrence occurred in two patients, stable disease in five, and progression of disease in five. The two patients with CR have had no recurrence for 44 and 33 months, respectively. IHS in one patient who underwent partial hepatectomy showed infiltration of CD8+ T cells and granzyme B in tumors, indicating that the dominant immune effector cells were cytotoxic T lymphocytes with tumor-killing activity.
This study demonstrated that HSP70-DCs therapy is both safe and feasible in patients with HCV-related HCC. Further clinical trials should be considered.
No preview · Article · May 2015 · Cancer Immunology and Immunotherapy
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to develop an accurate predictive system for prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. We pooled data of clinicopathological features of 234 HCC patients who underwent curative hepatectomy. On the basis of the pooled data, we established a simple predictive staging system (PS score) scored by the mathematical product of tumor number and size, and degree of liver function. We compared the prognostic abilities of the PS score (score 0-3) with those of six well-known clinical staging systems. Then, we found that there were significant differences (P<0.05) in both disease-free survival (DFS) and overall survival (OS) between patients with different PS scores (PS score 0 vs. 1; PS score 1 vs. 2), and there was a significant difference in DFS, but not OS, between patients with PS score 2 and those with PS score 3. Moreover, the PS score had smaller values of the Akaike information criterion for both DFS and OS than any of the six well-known clinical staging systems. These results suggest that the PS score serves as a simple, accurate predictor for the prognosis of HCC patients after hepatectomy.
Full-text · Article · Dec 2014 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: It is important to ensure restricted operation fields and operation maneuvers in the surgical resection of liver tumors located under the diaphragm, especially those near the hepatic vein and IVC. Here we describe resection and ablation using thoracoscopy for tumors under the diaphragm after preoperative three-dimensional(3D)simulation.
Preoperative 3D images were reformatted preoperatively using a 3D software tool(Virtual Place; AZE, Japan). These images simulate the thoracoscopic view on the surface of the diaphragm, enabling us to confirm the tumor location and choose optimal port position.
We performed thoracoscopic surgery in 5 patients(4 with HCC and 1 with a metastatic tumor)after the simulation. In all cases, we were able to safely confirm the tumor locations and perform the surgeries.
Preoperative 3D simulation makes it easy to determine the optimal port position for the thoracoscope and confirm the tumor location. The approach through the diaphragm using thoracoscpy is useful since it does not require liver mobilization.
No preview · Article · Nov 2014 · Gan to kagaku ryoho. Cancer & chemotherapy
[Show abstract][Hide abstract] ABSTRACT: We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma.
N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects.
Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis.
Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ.
ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.
No preview · Article · Mar 2014 · Annals of surgery
[Show abstract][Hide abstract] ABSTRACT: To evaluate the safety of combination vaccine treatment of multiple peptides, phase I clinical trial was conducted for patients with advanced colorectal cancer using five novel HLA-A*2402-restricted peptides, three peptides derived from oncoantigens, ring finger protein 43 (RNF43), 34 kDa-translocase of the outer mitochondrial membrane (TOMM34), and insulin-like growth factor-II mRNA binding protein 3 (KOC1), and the remaining two from angiogenesis factors, vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2.
Eighteen HLA- A*2402-positive colorectal cancer patients who had failed to standard therapy were enrolled in this study. 0.5 mg, 1.0 mg or 3.0 mg each of the peptides was mixed with incomplete Freund's adjuvant and then subcutaneously injected at five separated sites once a week. We also examined possible effect of a single site injection of "the cocktail of 5 peptides" on the immunological responses. ELISPOT assay was performed before and after vaccinations in the schedule of every 4 weeks.
The vaccine treatment using multiple peptides was well tolerated without any severe treatment-associated systemic adverse events. Dose-dependent induction of peptide-specific cytotoxic T lymphocytes was observed. The single injection of "peptides cocktail" did not diminish the immunological responses. Regarding the clinical outcome, one patient achieved complete response and 6 patients revealed stable disease for 4 to 7 months. The median overall survival time (MST) was 13.5 months. Patients, in which we detected induction of cytotoxic T lymphocytes specific to 3 or more peptides, revealed significantly better prognosis (MST; 27.8 months) than those with poorer immune responses (MST; 3.7 months) (p = 0.032).
Our cancer vaccine treatment using multiple peptides is a promising approach for advanced colorectal cancer with the minimum risk of systemic adverse reactions.Clinical trial registration: UMIN-CTR number UMIN000004948.
Full-text · Article · Mar 2014 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma.
The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft.
Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days).
Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.
No preview · Article · Nov 2013 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: The patient was a 69-year-old woman with elevated levels of hepatobiliary enzymes. An abdominal computed tomography (CT) scan revealed an enhanced mass in the liver hilum with dilatation of the intrahepatic bile duct. We diagnosed hilar cholangiocarcinoma and administered neoadjuvant chemoradiation therapy because of the possibility of tumor cells remaining at the surgical margins. Radical surgery was performed and pathological examination showed the tumor to be Grade 2b according to the Oboshi-Shimosato classification. Although postoperative bile leakage and intra-abdominal abscess were observed, the patient was discharged on day 82 after surgery. The patient is still alive without recurrence at 17 months after the surgery. Neoadjuvant chemoradiation therapy has the potential to obtain a negative surgical margin in patients with hilar cholangiocarcinoma, which is likely to be positive for cancer cells at the surgical margin in preoperative diagnosis.
No preview · Article · Nov 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
[Show abstract][Hide abstract] ABSTRACT: A 61-year-old man who complained of right hypochondralgia was diagnosed as hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) infection. The tumor was located in the right lobe and S3, and the tumor thrombus extended into the main portal and left portal veins. Preoperatively, real-time tumor-tracking radiation therapy was performed on the tumor thrombus (20 Gy/4 Fr),after vessel coils were placed at the anterior hepatic artery as a marker for the radiation. Ten days after radiation therapy, extended right hepatectomy with thrombectomy and S3 partial hepatectomy were performed. There were no postsurgical complications, and intrahepatic artery infusion chemotherapy was performed. The patient was alive with no recurrences 20 months after surgery. Radiation therapy before hepatectomy is an effective treatment for portal venous tumor thrombus in HCC.
No preview · Article · Nov 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Curative resection can be achieved in some cases of multiple liver metastases that are initially unresectable by multistage hepatectomy. We report the case of a patient who underwent 2 hepatectomy procedures for liver metastases of advanced colon cancer after conversion chemotherapy and 2-stage hepatectomy; this treatment resulted in long-term survival.
No preview · Article · Nov 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) often exhibits a poor prognosis due to metastatic spread caused by portal vein invasion (PVI). In the present study, we attempted to identify a novel therapeutic target related to PVI of HCC. Based on pooled genomic data, we identified RD RNA binding protein (RDBP), a member of the negative elongation factor (NELF) transcription elongation regulatory complex, to be preferentially overexpressed in HCC with PVI. We used quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-histochemical analyses to investigate the relationship between RDBP mRNA and protein with metastatic potential in sample sets of hepatitis C virus (HCV)-related HCC and corresponding non-HCC liver tissues. We also used the small interfering RNA technique to examine the role of RDBP in invasion and proliferation of HCC cells in vitro. Our data showed that both mRNA and protein levels of RDBP were significantly higher in HCC compared to non-HCC liver tissue, and that these levels were also significantly higher in HCC with PVI compared to HCC without PVI. Multivariate analysis revealed that RDBP protein levels were an independent risk factor for early intrahepatic recurrence of HCC within 2 years of surgery. Knockdown of RDBP protein significantly inhibited the proliferation and invasion of cells in vitro. These data demonstrate that RDBP is related to the metastatic potential of HCC, suggesting a possible candidate for prevention of HCC cell metastasis.
No preview · Article · May 2012 · Oncology Reports
[Show abstract][Hide abstract] ABSTRACT: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM).
After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues.
Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation.
Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.
Full-text · Article · Apr 2012 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer is a common disease which requires improved therapeutic options. We performed a genome-wide exploration using cDNA microarray profiling, and successfully identified a new tumor-associated antigen (TAA) that can induce potent cytotoxic T lymphocytes specific to tumor cells, i. e., RNF43, KOC1, TOMM34, VEGFR1 and VEGFR2. We conducted a phase I dose escalation study using these five tumor-associated antigen epitope peptides for colorectal cancer patients. For a breakthrough in immunological tumor escape mechanisms, immuno-chemo-combined therapy was conducted. Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to upregulate tumor-associated antigen expression, and downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy. We conducted a phase II trial, with administration of epitope peptides in combination with chemotherapy (5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX), to evaluate immunologic and clinical responses.
[Show abstract][Hide abstract] ABSTRACT: There are few blood tests for an efficient detection of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection.
The abilities of quantitative analyses of 7 genes hypermethylation in serum DNA, α-fetoprotein (AFP) and prothrombin-induced vitamin K absence II (PIVKA-II), and various combinations to detect HCC were evaluated in a training cohort of 164 HCV-infected patients (108 HCCs; 56 non-HCCs). An optimal hybrid detector, built using data for 2 methylated genes (SPINT2 and SRD5A2), AFP, and PIVKA-II, achieved the most satisfactory ability to detect HCC in the training cohort. We evaluated the ability of the optimal hybrid detector to detect HCC in an independent validation cohort of 258 consecutive HCV-infected patients (112 HCCs; 146 non-HCCs) who were newly enrolled in 4 distinct institutes.
In the validation cohort of 258 patients, accuracy, sensitivity, and specificity of the hybrid detector for detection of HCC were 81.4%, 73.2%, and 87.7%, respectively. Notably, even when detecting HCC ≤ 2 cm in diameter, the hybrid detector maintained markedly high abilities (84.6% accuracy, 72.2% sensitivity, 87.7% specificity). Youden's index (sensitivity+specificity - 1) for HCC ≤ 2cm was 0.60, vastly much superior to the 0.39 for AFP at a cut-off value of 20 ng/ml and the 0.28 for PIVKA-II at a cut-off value of 40 mAU/ml.
These results show that the optimal hybrid blood detector can detect HCV-related HCC more accurately.
No preview · Article · Sep 2010 · Clinica chimica acta; international journal of clinical chemistry
[Show abstract][Hide abstract] ABSTRACT: Prognosis of hepatocellular carcinoma (HCC) remains poor because of high recurrence rate. We examined preoperatively the methylated CCND2 gene levels present in the serum following release from HCC cells as a prognosis predictor in patients undergoing curative hepatectomy.
Quantitative real-time RT-PCR and quantitative methylation-specific PCR were used to measure methylated CCND2 gene and its mRNA levels.
The CCND2 mRNA levels were down-regulated in HCC with early intrahepatic recurrence (IHR) within 1year of curative hepatectomy. We also identified that this down-regulation was due to promoter hypermethylation. In 70 HCC patients who underwent curative hepatectomy, 39 patients sero-positive for the methylated CCND2 gene (>70pg/ml serum) exhibited a significantly shorter disease-free survival (DFS) period (P=0.02) than the 31 patients who were sero-negative for the methylated CCND2 gene. None of the sero-negative patients demonstrated early IHR, and this method of serum testing did not produce any false-negative predictions for early IHR. Multivariate analysis showed that the serum level of methylated CCND2 was an independent risk factor for DFS (hazard ratio of 1.866, 95% CI: 1.106-3.149).
Methylated CCND2 gene in the serum serves as a prognosis predictor of HCC after curative hepatectomy.
No preview · Article · Apr 2010 · Clinica chimica acta; international journal of clinical chemistry
[Show abstract][Hide abstract] ABSTRACT: We report a case of ascending colon cancer successfully treated for synchronous liver metastases with mFOLFOX6 after a resection of the primary tumor. A 79-year-old woman was diagnosed as having an ascending colon cancer with synchronous liver metastases. After right hemicolectomy, she was treated with mFOLFOX6. A partial response was observed after the fifth course and CEA decreased to a normal range (8 ng/mL). A complete response was observed after the ninth course and the treatment finished at the twelfth course. Sequentially, she was treated with UFT/LV/PSK after three courses of FOLFIRI regimen. The patient is alive without recurrence.
No preview · Article · Nov 2009 · Gan to kagaku ryoho. Cancer & chemotherapy